The AAPS Journal

, Volume 12, Issue 3, pp 397–406 | Cite as

The Use of Biorelevant Dissolution Media to Forecast the In Vivo Performance of a Drug

Review Article Theme: Role of Dissolution in QbD and Drug Product Life Cycle


Simulation of gastrointestinal conditions is essential to adequately predict the in vivo behavior of drug formulations. To reduce the size and number of human studies required to identify a drug product with appropriate performance in both the fed and fasted states, it is advantageous to be able to pre-screen formulations in vitro. The choice of appropriate media for such in vitro tests is crucial to their ability to correctly forecast the food effect in pharmacokinetic studies. The present paper gives an overview of the development and composition of biorelevant dissolution media that can be used for the in vitro simulation of different dosing conditions (fasted and fed states). In addition, the application of these media to predicting food effects is described in several case examples.

Key words

BA biorelevant media dissolution fasted state fed state food effects 


  1. 1.
    Dressman JB, Reppas C. In vitroin vivo correlations for lipophilic, poorly water-soluble drugs. Eur J Pharm Sci. 2000;11 Suppl 2:73–80.CrossRefGoogle Scholar
  2. 2.
    Noyes AA, Whitney WR. The rate of solution of solid substances in their own solutions. J Am Chem Soc. 1897;19:930–4.CrossRefGoogle Scholar
  3. 3.
    Nernst W. Theorie der Reaktionsgeschwindigkeit in heterogenen Systemen. Z Physikal Chemie. 1904;47:52–5.Google Scholar
  4. 4.
    Horter D, Dressman JB. Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract. Adv Drug Del Rev. 1997;25(April):3–14.CrossRefGoogle Scholar
  5. 5.
    Dressman JB, Amidon GL, Reppas C, Shah VP. Dissolution testing as a prognostic tool for oral drug absorption: immediate release dosage forms. Pharm Res. 1998;15(1):11–22.CrossRefPubMedGoogle Scholar
  6. 6.
    Ozturk SS, Palsson BO, Dressman JB. Dissolution of ionizable drugs in buffered and unbuffered solutions. Pharm Res. 1988;5(5):272–82.CrossRefPubMedGoogle Scholar
  7. 7.
    Shah VP. Dissolution: a quality control test vs a bioequivalence test. Dissolution Technologies. 2001;8(4):6–7.Google Scholar
  8. 8.
    FDA. Guidance for industry: dissolution testing of immediate release solid oral dosage forms. Rockville MD, USA: U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER); 1997.Google Scholar
  9. 9.
    FDA. Guidance for industry: extended release oral dosage forms: development, evaluation, and application of in vitro/in vivo correlations. Rockville MD, USA: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER); 1997.Google Scholar
  10. 10.
    FDA. Guidance for industry: waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system. Rockville MD, USA: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER); 2000.Google Scholar
  11. 11.
    Dressman JB, Berardi RR, Dermentzoglou LC, Russell TL, Schmaltz SP, Barnett JL, et al. Upper gastrointestinal (GI) pH in young, healthy men and women. Pharm Res. 1990;7(7):756–61.CrossRefPubMedGoogle Scholar
  12. 12.
    Efentakis M, Dressman JB. Gastric juice as a dissolution medium: surface tension and pH. Eur J Drug Metab Pharmacokinet. 1998;23(2):97–102.PubMedCrossRefGoogle Scholar
  13. 13.
    Finholt P, Solvang S. Dissolution kinetics of drugs in human gastric juice—the role of surface tension. J Pharm Sci. 1968;57(8):1322–6.CrossRefPubMedGoogle Scholar
  14. 14.
    Finholt P, Gundersen H, Smit A, Petersen H. Surface tension of human gastric juice. Medd Norsk Farm Selsk. 1978;41:1–14.Google Scholar
  15. 15.
    Youngberg CA, Berardi RR, Howatt WF, Hyneck ML, Amidon GL, Meyer JH, et al. Comparison of gastrointestinal pH in cystic fibrosis and healthy subjects. Dig Dis Sci. 1987;32:472–80.CrossRefPubMedGoogle Scholar
  16. 16.
    USP. USP 24. Rockville MD: United States Pharmacopeia Convention, Inc.; 2002.Google Scholar
  17. 17.
    Gray VA, Dressman J. Change of pH requirements for simulated intestinal fluid TS. Pharmacopeial Forum. 1996;22(1):1943–5.Google Scholar
  18. 18.
    Klein S, Reppas C, Dressman JB. In vitro methods to predict food effects. In: Amidon G, Lesko L, Midha K, Shah V, Hilfinger J, editors. International bioequivalence standards: a new era. Ann Arbor: TSRL Inc.; 2006.Google Scholar
  19. 19.
    Galia E, Horton J, Dressman JB. Albendazole generics—a comparative in vitro study. Pharm Res. 1999;16(12):1871–5 (in process citation).CrossRefPubMedGoogle Scholar
  20. 20.
    Luner PE, VanDer Kamp D. Wetting characteristics of media emulating gastric fluids. Int J Pharm. 2001;212:81–91.CrossRefPubMedGoogle Scholar
  21. 21.
    Vertzoni M, Pastelli E, Psachoulias D, Kalantzi L, Reppas C. Estimation of intragastric solubility of drugs: in what medium? Pharm Res. 2007;24(5):909–17.CrossRefPubMedGoogle Scholar
  22. 22.
    Vertzoni M, Dressman J, Butler J, Hempenstall J, Reppas C. Simulation of fasting gastric conditions and its importance for the in vivo dissolution of lipophilic compounds. Eur J Pharm Biopharm. 2005;60(3):413–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Klein S. The mini paddle apparatus—a useful tool in the early developmental stage? Experiences with immediate release dosage forms. Dissolution Technologies. 2006;13(4):6–11.Google Scholar
  24. 24.
    Klein S, Shah V. A standardized mini paddle apparatus as an alternative to the standard paddle. Aaps Pharmscitech. 2008;9(4):1179–84.CrossRefPubMedGoogle Scholar
  25. 25.
    Greenwood D. Small intestinal pH and buffer capacity: implications for dissolution of ionizable compounds. Doctoral thesis, University of Michigan, Ann Arbor; 1994Google Scholar
  26. 26.
    Galia E, Nicolaides E, Horter D, Lobenberg R, Reppas C, Dressman JB. Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs. Pharm Res. 1998;15(5):698–705.CrossRefPubMedGoogle Scholar
  27. 27.
    Hofmann AF, Small DM. Detergent properties of bile salts: correlation with physiological function. Annu Rev Med. 1967;18:333–76.CrossRefPubMedGoogle Scholar
  28. 28.
    Carey MC, Small DM. Micelle formation by bile salts. Physical–chemical and thermodynamic considerations. Arch Intern Med. 1972;130(4):506–27.CrossRefPubMedGoogle Scholar
  29. 29.
    Redinger RN, Small DM. Bile composition, bile salt metabolism and gallstones. Arch Intern Med. 1972;130(4):618–30.CrossRefPubMedGoogle Scholar
  30. 30.
    Galia E. Physiologically based dissolution tests. Doctoral thesis, Johann Wolfgang Goethe University, Frankfurt; 1999.Google Scholar
  31. 31.
    Marques M. Dissolution media simulating fasted and fed states. Dissolution Technologies. 2004;11(2):16.Google Scholar
  32. 32.
    Ashby LJ, Beezer AE, Buckton G. In vitro dissolution testing of oral controlled release preparations in the presence of artificial foodstuffs. I. Exploration of alternative methodology: microcalorimetry. Int J Pharm. 1989;51:245–51.CrossRefGoogle Scholar
  33. 33.
    Buckton G, Beezer AE, Chatham SM, Patel KK. In vitro dissolution testing of oral controlled release preparations in the presence of artificial foodstuffs. II. Probing drug/food interactions using microcalorimetry. Int J Pharm. 1989;56:151–7.CrossRefGoogle Scholar
  34. 34.
    Kraemer J. Korrelation biopharmazeutischer in vivo und in vitro Daten von Theophyllin und Verapamil Retardpräparaten. Doctoral thesis, Ruprecht-Karls-Universität, Heidelberg; 1995Google Scholar
  35. 35.
    Ross. The Ross medical nutritional system. Product Handbook. Columbus, USA; 1993.Google Scholar
  36. 36.
    Junginger HE, Verhoeven J, Peschier LJC. A new in vitro model to detect interactions between controlled release dosage forms and food. Acta Pharm Technol. 1990;36(3):155–60.Google Scholar
  37. 37.
    FDA. Guidance for industry: food-effect bioavailability and bioequivalence studies. In: Draft guidance. Rockville MD, USA: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER); 1997.Google Scholar
  38. 38.
    Klein S, Butler J, Hempenstall JM, Reppas C, Dressman JB. Media to simulate the postprandial stomach. I. Matching the physicochemical characteristics of standard breakfasts. J Pharm Pharmacol. 2004;56(5):605–10.CrossRefPubMedGoogle Scholar
  39. 39.
    Macheras P, Koupparis M, Tsaprounis C. Drug dissolution studies in milk using the automated flow injection serial dynamic dialysis technique. Int J Pharm. 1986;33:125–36.CrossRefGoogle Scholar
  40. 40.
    Macheras P, Koupparis M, Apostolelli E. Dissolution of 4 controlled-release theophylline formulations in milk. Int J Pharm. 1987;36:3–79.CrossRefGoogle Scholar
  41. 41.
    Macheras P, Koupparis M, Antimisaris S. An in vitro model for exploring CR theophylline–milk fat interactions. Int J Pharm. 1989;54:123–30.CrossRefGoogle Scholar
  42. 42.
    Klein S. Biorelevant dissolution test methods for modified release dosage forms. Frankfurt: Shaker; 2005.Google Scholar
  43. 43.
    Fordtran JS, Locklear TW. Ionic constituents and osmolality of gastric and small-intestinal fluids after eating. Am J Dig Dis. 1966;11(7):503–21.CrossRefPubMedGoogle Scholar
  44. 44.
    Klein S, Stippler E, Wunderlich M, Dressman J. Development of dissolution tests on the basis of gastrointestinal physiology. In: Dressman J, Kraemer J, editors. Pharmaceutical dissolution testing. Boca Raton: Taylor & Francis; 2005. p. 193–228.CrossRefGoogle Scholar
  45. 45.
    Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413–20.CrossRefPubMedGoogle Scholar
  46. 46.
    Stegemann S, Leveiller F, Franchi D, de Jong H, Linden H. When poor solubility becomes an issue: from early stage to proof of concept. Eur J Pharm Sci. 2007;31(5):249–61.CrossRefPubMedGoogle Scholar
  47. 47.
    Stippler E. Biorelevant dissolution test methods to asses bioequivalence of drug products. Doctoral thesis, Johann Wolfgang Goethe University, Frankfurt; 2004Google Scholar
  48. 48.
    WHO. Proposal to waive in vivo bioequivalence requirements for the WHO model list of essential medicines immediate release, solid oral dosage forms. Working document QAS/04.109/Rev. 1. World Health Organisation, Geneva; 2005.Google Scholar
  49. 49.
    Sweetman SC. Martindale—the complete drug reference. 33rd ed. London: Pharmaceutical Press; 2002.Google Scholar
  50. 50.
    Sunesen VH, Vedelsdal R, Kristensen HG, Christrup L, Mullertz A. Effect of liquid volume and food intake on the absolute bioavailability of danazol, a poorly soluble drug. Eur J Pharm Sci. 2005;24(4):297–303.CrossRefPubMedGoogle Scholar
  51. 51.
    Bakatselou V, Oppenheim RC, Dressman JB. Solubilization and wetting effects of bile salts on the dissolution of steroids. Pharm Res. 1991;8(12):1461–9.CrossRefPubMedGoogle Scholar
  52. 52.
    Swoboda W, Bohrn E. Steroid treatment of adolescent gynecomastia with danazol. Wiener Medizinische Wochenschrift. 1981;131(5):127–32.PubMedGoogle Scholar
  53. 53.
    Charman WN, Rogge MC, Boddy AW, Berger BM. Effect of food and a monoglyceride emulsion formulation on danazol bioavailability. J Clin Pharmacol. 1993;33(4):381–6.PubMedGoogle Scholar
  54. 54.
    Lindenberg M, Kopp S, Dressman JB. Classification of orally administered drugs on the World Health Organization model list of essential medicines according to the biopharmaceutics classification system. Eur J Pharm Biopharm. 2004;58(2):265–78.CrossRefPubMedGoogle Scholar
  55. 55.
    Sidhu S, Malhotra S, Garg SK. Influence of high fat diet (butter) on pharmacokinetics of phenytoin and carbamazepine. Methods Find Exp Clin Pharmacol. 2004;26(8):634–8.CrossRefPubMedGoogle Scholar
  56. 56.
    Melander A, Brante G, Johansson O, Lindberg T, Wahlinboll E. Influence of food on the absorption of phenytoin in man. Eur J Clin Pharmacol. 1979;15(4):269–74.CrossRefPubMedGoogle Scholar
  57. 57.
    Sekikawa H, Nakano M, Takada M, Arita T. Influence of dietary-components on the bioavailability of phenytoin. Chem Pharm Bull. 1980;28(8):2443–9.PubMedGoogle Scholar
  58. 58.
    Russell TL, Berardi RR, Barnett JL, Dermentzoglou LC, Jarvenpaa KM, Schmaltz SP, et al. Upper gastrointestinal pH in seventy-nine healthy, elderly, North American men and women. Pharm Res. 1993;10(2):187–96.CrossRefPubMedGoogle Scholar
  59. 59.
    Buchanan CM, Buchanan NL, Edgar KJ, Klein S, Little JL, Ramsey MG, et al. Pharmacokinetics of itraconazole after intravenous and oral dosing of itraconazole–cyclodextrin formulations. J Pharm Sci. 2007;96(11):3100–16.CrossRefPubMedGoogle Scholar
  60. 60.
    Willems L, van der Geest R, de Beule K. Itraconazole oral solution and intravenous formulations: a review of pharmacokinetics and pharmacodynamics. J Clin Pharm Ther. 2001;26(3):159–69.CrossRefPubMedGoogle Scholar
  61. 61.
    Jantratid E, Janssen N, Reppas C, Dressman JB. Dissolution media simulating conditions in the proximal human gastrointestinal tract: an update. Pharm Res. 2008;25(7):1663–76.CrossRefPubMedGoogle Scholar
  62. 62.
    Kalantzi L, Goumas K, Kalioras V, Abrahamsson B, Dressman JB, Reppas C. Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability/bioequivalence studies. Pharm Res. 2006;23(1):165–76.CrossRefPubMedGoogle Scholar
  63. 63.
    Porter CJH, Trevaskis NL, Charman WN. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nature Reviews Drug Discovery. 2007;6(3):231–48.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2010

Authors and Affiliations

  1. 1.Institute of Pharmacy, Biopharmacy and Pharmaceutical TechnologyErnst Moritz Arndt UniversityGreifswaldGermany

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